Sustained catecholaminergic stress is known to promote heart failure (Cohn et al., 1984 “Plasma Norepinephrine as a Guide to Prognosis in Patients with Chronic Congestive Heart Failure” New England Journal of Medicine, 311: 819-823). In contrast to this, short-term catecholaminergic stimulation (e.g. by physical exercise) promotes cardiac health (Keteyian et al, 2010 “Clinical Role of Exercise Training in the Management of Patients with Chronic Heart Failure” Journal of Cardiopulmonary Rehabilitation and Prevention, 30:67-76). Thus, there appear to be different signaling pathways downstream of the β-adrenergic receptor mediating cardioprotective and pathophysiological effects of β-adrenergic receptor stimulation. One consequence of sustained catecholaminergic stress is myocardial remodeling which causes or exacerbates heart failure. Thus, therapeutic means for influencing said signaling pathways are desirable.
Full-length histone deacetylase 4 (HDAC4) is proteolytically processed by a previously unknown enzyme yielding an N-terminal fragment (HDAC4-NT) comprising 201 amino acids. In vitro, HDAC4-NT selectively represses myocyte enhancer factor 2 (MEF2) (Backs et al., 2011, “Selective repression of MEF2 Activity by PKA-dependent Proteolysis of HDAC4”, Journal of Cell Biology, 195: 403-415).
Abhydrolase containing domain 5 (ABHD5, also known as “comparative gene identification-58” (CGI-58)) is a protein which has been previously known to be involved in lipid metabolism (Grannemann et al., 2009 “Perilipin controls Lipolysis by regulating the Interactions of AB-hydrolase Containing 5 (Abhd5) and Adipose Triglyceride Lipase (Atgl)”, The Journal of Biological Chemistry 284: 34538-34544). Mutations of ABHD5 cause the Chanarin-Dorfman syndrome, a rare genetic disease characterized by excessive accumulation of triacylglycerol in multiple tissues (Lass et al., 2006 “Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome” Cell Metabolism 3: 309-319). It has not been implicated in the regulation of cardiac remodeling.
Thus, the problem underlying the present invention can be viewed as the provision of novel means and methods for the treatment and prevention of heart failure.